EP2486042B1 - Bicyclic heterocycles and their use as ccr2 receptor antagonists - Google Patents

Bicyclic heterocycles and their use as ccr2 receptor antagonists Download PDF

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EP2486042B1
EP2486042B1 EP10766012.8A EP10766012A EP2486042B1 EP 2486042 B1 EP2486042 B1 EP 2486042B1 EP 10766012 A EP10766012 A EP 10766012A EP 2486042 B1 EP2486042 B1 EP 2486042B1
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hydroxy
alkyl
methyl
oxo
carboxylic acid
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EP2486042A1 (en
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Johannes Aebi
Alfred Binggeli
Luke Green
Guido Hartmann
Hans P. Maerki
Patrizio Mattei
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F Hoffmann La Roche AG
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • WO2009010429 and WO2009043747 disclose heterocyclic compounds for use as antagonists of CCR2 receptor, CCR5 receptor and/or CCR3 receptor.
  • the invention is concerned with novel bicyclic compounds of formula (I), wherein
  • Certain compounds of formula (I) may exist in more than one tautomeric form.
  • the present invention encompasses all such tautomers, as well as mixtures thereof.
  • Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium and attempts to isolate an individual tautomers usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates while; in phenols, the enol form predominates.
  • the invention is concerned with a process and an intermediate for the manufacture of the above compounds, pharmaceutical preparations which contain such compounds, the use of these compounds for the production of pharmaceutical preparations.
  • the compounds of formula (I) are CCR2 receptor (Chemokine Receptor 2/Monocyte chemotactic protein 1 receptor) antagonists and/or also CCR5 receptor (Chemokine Receptor 5) and/or CCR3 receptor (Chemokine Receptor 3) antagonists.
  • Chemokines are a family of small, secreted proinflammatory cytokines functioning as chemoattractants for leukocytes. They promote trafficking of leukocytes from vascular beds into surrounding tissues in response to inflammatory signals.
  • Chemotaxis starts upon chemokine binding to receptors (GPCRs) by initiating signaling pathways involving increased Ca-flux, inhibition of cAMP production, rearrangements of the cytoskeleton, activation of integrins and of cell motility processes and an increase in the expression of adhesion proteins.
  • Proinflammatory chemokines are considered to be involved in the development of atherosclerosis and other important diseases with inflammatory components like rheumatoid arthritis, asthma, multiple sclerosis, transplant rejection and ischemia reperfusion injury with specific prominent effects in nephropathy and peripheral vascular diseases.
  • Monocyte Chemotactic protein 1 is considered to be the major stimulated chemokine mediating inflammatory processes in these diseases through the CCR2 receptor on monocytes and on some T lymphocytes.
  • MCP-1 / CCR2 are in discussion to be related to the progression of the metabolic syndrome to more severe stages of obese and diabetic diseases.
  • CCR2 has also been linked to HIV infection, and consequently the course of autoimmune diseases, through its heterodimerization with CCR5 which has a role as coreceptor for viral entry into host cells.
  • CCR2 can be a target of a new medicine for treatment of peripheral vascular diseases, and more specifically for treatment of patients with critical limb ischemia. Furthermore, study results and experiences from the development of a new CCR2 medicine for this indication may facilitate a follow-up development for treatment of atherosclerosis.
  • MCP-1 and CCR2 ko mice in wt or apoE-/- or LDL-R-/- backgrounds showing that the MCP-1/CCR2 pathway is essential for monocyte / macrophage recruitment, and also for intimal hyperplasia and the formation and stability of atherosclerotic lesions.
  • numerous reports describe involvement of the MCP-1 / CCR2 pathway in man post injury and in various inflammatory processes, including such in vascular beds.
  • the present invention provides the novel compounds of formula (I) which are CCR2 receptor antagonists, with some antagonist activity also at CCR3 and CCR5.
  • Certain compounds of formula (I) may exist in more than one tautomeric form.
  • the present invention encompasses all such tautomers, as well as mixtures thereof.
  • halogen refers to fluoro, chloro, bromo or iodo.
  • Preferred "halogen” groups are fluoro or chloro.
  • C 1-6 alkyl alone or in combination with other groups, means a branched or straight-chain monovalent alkyl radical, having one to six carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl. C 1-4 alkyl or C 1-3 alkyl is more preferred.
  • C 2-6 alkyl means the same as a “C 1-6 alkyl”, except that the C 2-6 alkyl has two to six carbon atoms; and the term “C 3-6 alkyl” means the same as a “C 1-6 alkyl”, except that the C 1-6 alkyl has three to six carbon atoms; etc.
  • C 1-20 alkyl means the same as a “C 1-6 alkyl”, except that that the C 1-20 alkyl has one to 20 carbon atoms.
  • C 1-20 alkylcarbonyloxy-C 1-6 alkyl refers to the group R b1 -C(O)-O-R b2 -, wherein R b2 is a C 1-6 alkylene and R b1 is a C 1-20 alkyl, as defined above.
  • C 1-20 alkoxycarbonyloxy-C 1-6 alkyl refers to the group R a3 -C(O)-O-R b3 -, wherein R b3 is a C 1-6 alkylene and R a3 is a C 1-20 alkoxy, as defined above.
  • C 1-6 alkoxy alone or in combination with other groups, means the group R'-O-, wherein R' is a C 1-6 alkyl.
  • C 1-6 alkoxy-carbonyl refers to the group R a1 -C(O)-, wherein R a1 is a C 1-6 alkoxy as defined above.
  • C 1-6 alkoxy-C 1-6 alkyl means a C 1-6 alkyl substituted by a C 1-6 alkoxy group, as defined herein.
  • C 1-6 alkoxy-carbonyloxy refers to the group R a2 -C(O)-O-, wherein R a2 is a C 1-6 alkoxy as defined above.
  • aryl alone or combination with other groups, means cyclic aromatic hydrocarbon radical consisting of one or more fused rings containing 6-14 carbon atoms, for example phenyl or naphthyl.
  • arylmethyl preferably means a phenyl-CH 2 - or a aphthyl-CH 2 radical.
  • phenyl-C 1-3 alkyl means a C 1-3 alkyl, as defined herein, substituted by phenyl.
  • arylcarbonyloxy-C 1-6 alkyl refers to the group R c1 -C(O)-O-R c2 -, wherein R c2 is a C 1-6 alkylene and R c1 is an aryl, as defined above
  • C 3-6 alkenyl alone or in combination with other groups, means a straight-chain or branched hydrocarbon residue comprising a carbon-carbon double bond, having three to six carbon atoms, provided that the carbon atom of the attachment point of the C 3-6 alkenyl to the rest of the molecule is not bonded to another carbon atom of the C 3-6 alkenyl by a carbon-carbon double bond.
  • An example of a C 3-6 alkenyl is 2-propenyl.
  • C 1-6 alkylene alone or in combination with other groups, means a branched or straight-chain saturated divalent hydrocarbon radical of one to six carbon atoms, such as methylene, ethylene, tetramethylethylene.
  • C 3-6 -alkynyl alone or in combination with other groups, means a straight-chain or branched hydrocarbon residue comprising a carbon-carbon triple bond, having three to six carbon atoms, provided that the carbon atom of the attachment point of the C 3-6 alkynyl to the rest of the molecule is not bonded to another carbon atom of the C 3-6 alkynyl by a carbon-carbon triple bond.
  • An example of a C 3-6 alkynyl is 2-propynyl.
  • carboxyl refers to a group -C(O)OH.
  • carbamoyl refers to a group -C(O)NH 2 .
  • C 3-7 cycloalkyl alone or in combination with other groups, means a saturated monovalent mono-cyclic hydrocarbon radical of three to seven ring carbons (e.g., cyclopropyl, cyclobutyl, or cyclohexyl).
  • C 3-7 cycloalkyl C 1-6 alkyl means a C 1-6 alkyl substituted by one or more, preferably one or two, C 3-7 cycloalkyl groups, as defined herein.
  • C 7-10 bicycloalkyl alone or in combination with other groups, means a saturated monovalent cyclic hydrocarbon radical of seven to ten ring carbons, having two rings, in which two or more ring carbon atoms of one ring are ring carbon atoms of the other ring (e.g., bicyclo[2.2.1]heptyl).
  • halo C 1-6 alkoxy alone or in combination with other groups, means a C 1-6 alkoxy substituted by one or more halogens. In particular embodiments the C 1-6 alkoxy is substituted by one to three halogens.
  • halo C 1-6 alkyl means a C 1-6 alkyl substituted by one or more of the same or different halogen atoms. Examples are 1-fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl. The most preferred "halo C 1-6 alkyl” is trifluoromethyl.
  • heteroaryl alone or combination with other groups, means an aromatic monocyclic- or bicyclic-aromatic radical of 5 to 10 ring atoms having one to three ring heteroatoms independently selected from N, O, and S, with the remaining ring atoms being C.
  • heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrimidinyl, pyrazolyl, pyrazinyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, imidazo[1,2-a]-pyridinyl, imidazo[2,1-b]thiazolyl, and the derivatives thereof.
  • pyridyl furany
  • heteroaryl-C 1-3 alkyl means a C 1-3 alkyl substituted by a heteroaryl, as defined herein.
  • heterocyclyl alone or combination with other groups, means a nonaromatic mono- or bi-cyclic radical of four to nine ring atoms in which one to three ring atoms are heteroatoms independently selected from N, O and S(O) n (where n is an integer from 0 to 2), with the remaining ring atoms being C.
  • the more preferred heterocyclyl is piperidyl or 6-aza-spiro[2,5]oct-6yl.
  • heterocyclyl-C 1-3 alkyl means a C 1-3 alkyl, substituted by one heterocyclyl, as defined herein.
  • hydroxy C 1-6 alkyl means C 1-6 alkyl substituted by one or more, preferably one hydroxy group(s).
  • di or di-C 1-6 alkyl substituted aminocarbonyl refers to a group - OC(O)NR b1 R c1 wherein at least one of R b1 and R c1 is C 1-6 alkyl and the other is hydrogen or C 1-6 alkyl.
  • di or di-C 1-6 alkyl substituted aminocarbonyloxy refers to a group - OC(O)NR v1 R v2 wherein at least one of R v1 and R v2 is C 1-6 alkyl and the other is hydrogen or C 1-6 alkyl.
  • acyl means R-C(O)-, in which R is a C 1-6 alkyl, halo C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkyl C 1-6 alkyl.
  • mono or di-C 1-6 alkyl substituted aminocarbonyloxy-C 1-6 alkyl means C 1-6 alkyl substituted by a mono or di-C 1-6 alkyl substituted aminocarbonyloxy, as defined above.
  • C 1-6 alkylsulfonyl means a C 1-6 alkyl-SO 2 - C 1-6 alkyl-SO- and C 1-6 alkyl-S-, respectively.
  • Preferred radicals for the chemical groups whose definitions are given above are those specifically exemplified in the Examples.
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • an "aryl group optionally substituted with an alkyl group” means that the alkyl may but need not be present, and the description includes situations where the aryl group is substituted with an alkyl group and situations where the aryl group is not substituted with the alkyl group.
  • “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a "pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • a therapeutically effective amount of a compound means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
  • the therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated.
  • the daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.
  • pharmaceutically acceptable carrier is intended to include any and all material compatible with pharmaceutical administration including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions of the invention are contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • a compound of the formula or “a compound of formula” or “compounds of the formula” or “compounds of formula” refers to any compound selected from the genus of compounds as defined by the formula.
  • Compounds of formula (I) can form pharmaceutically acceptable acid addition salts.
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • any variable e.g., R 1 , R 2
  • its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations ofsubstituents and/or variables are permissible only if such compounds result in chemically stable compounds.
  • the present invention provides compound of formula (I), wherein
  • the compounds of formula (I) possess two or more asymmetric centers. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof, as well as individual epimers and mixture thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992 ).
  • heterocyclyl formed by R 6 and R 7 together with the nitrogen atom to which they are attached, is piperidyl or pyrrolidinyl, and said piperidyl and pyrrolidinyl being optionally substituted by one or two substituents independently selected from the group consisting of halogen, hydroxy, C 1-6 alkyl and hydroxy C 1-6 alkyl, and/or
  • the heterocyclyl formed by R 6 and R 7 is preferably piperidyl or pyrrolidinyl, and said piperidyl and pyrrolidinyl being optionally substituted by one or two substituents independently selected from the group consisting of hydroxy, C 1-6 alkyl and hydroxy C 1-6 alkyl, and/or one of the ring carbon atoms of said piperidyl and pyrrolidinyl formed by R 6 and R 7 is also shared by a C 3-7 cycloalkyl, ring.
  • R 6 and R 7 together with the nitrogen atom to which they are attached form a mono spiro-heterocyclyl such as 6-aza-spiro[2,5]oct-6-yl, 5-azaspiro[2.5]oct-5-yl, 7-aza-spiro[3.5]non-7-yl, 8-aza-spiro[4.5]dec-8-yl, 1,8-diazaspiro[4.5]dec-8-yl, 1,3,8-triaza-spiro[4.5]dec-8-yl, 2,8-diaza-spiro[4.5]dec-8-yl, 1-oxa-3,8-diaza-spiro[4.5]dec-8-yl, 1-oxa-8-aza-spiro[4.5]dec-8-yl, 2-oxa-8-aza-spiro[4.5]dec-8-yl, 2-oxa-7-aza-spiro[3.5]non
  • the spiro heterocyclyl is 6-azaspiro[2,5]oct-6-yl wherein the spiro-heterocyclyl ring is optionally substituted by one to two substituents independently selected from the group consisting of fluoro, hydroxy or C 1-6 alkyl.
  • the spiro heterocyclyl is 6-aza-spiro[2,5]oct-6-yl wherein the spiroheterocyclyl ring is optionally substituted by one to two substituents independently selected from the group consisting of hydroxy or C 1-6 alkyl.
  • R 6 and R 7 together with the nitrogen atom to which they are attached form especially (S)-4-hydroxy-6-aza-spiro[2,5]oct-6-yl.
  • the inventtion provides a compound of formula (I'): wherein A, L, E, F, G, V, W, n, R 1 , R 2 , R 3 , R 4 , R 5 , R d are as defined above.
  • the inventtion provides a compound of formula (I"): wherein A, L, E, F, G, V, W, R 1 , R 2 , R d are as defined above.
  • A, E, F, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , V, W and n are as defined before.
  • the reaction is typically carried out in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone, dimethyl sulfoxide, acetonitrile and mixtures thereof at temperatures between 0°C and 120°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine, and/or 4-(dimethylamino)pyridine.
  • aprotic solvents such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone, dimethyl sulfoxide, acetonitrile and mixtures thereof at temperatures between 0°C and 120°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine, and/or 4-(dimethylamino)pyridine.
  • the reaction is typically carried out in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone, dimethyl sulfoxide, acetonitrile and mixtures thereof at temperatures between 0°C and 120°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine, and/or 4-(dimethylamino)pyridine.
  • aprotic solvents such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone, dimethyl sulfoxide, acetonitrile and mixtures thereof at temperatures between 0°C and 120°C in the presence or absence of a base such as tri
  • aprotic solvents such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between 0°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine, and/or 4-(dimethylamino)pyridine, and in the presence of a coupling agent such as N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphat
  • reagents for the formation of the acyl chloride are thionyl chloride, phosphorous pentachloride, oxalyl chloride or cyanuric chloride, and the reaction is generally conducted in the absence of a solvent or in the presence of an aprotic solvent like dichloromethane, toluene or acetone.
  • a base can optionally be added, like for example pyridine, triethylamine, diisopropylethylamine or 4-methylmorpholine, and catalytic amounts of N,N-dimethylformamide may be used.
  • the obtained cinnamylchloride can be isolated or reacted as such with amine 1 in an aprotic solvent, like dichloromethane, tetrahydrofuran or acetone, in the presence of a base.
  • Typical bases are triethylamine, 4-methylmorpholine, pyridine, diisopropylethylamine or 4-(dimethylamino)pyridine or mixtures thereof.
  • Compounds of formula (Id) can be from secondary amine 1 by reaction with halide A-Hal (Hal is F, Cl, Br, or I) or boronic acid A-B(OH) 2 , using methods and reagents known in the art.
  • the reaction can be performed with halide A-Hal at temperatures between 20°C and 200°C, in the presence of a base, e. g., potassium carbonate, cesium carbonate or triethylamine, in a solvent such as acetonitrile, N,N-dimethylformamide or N-methylpyrrolidinone, optionally under microwave irradiation.
  • a base e. g., potassium carbonate, cesium carbonate or triethylamine
  • a solvent such as acetonitrile, N,N-dimethylformamide or N-methylpyrrolidinone, optionally under microwave irradiation.
  • the reaction can be performed with halide A-Hal in the presence of a copper(I) salt, e. g., copper(I)iodide, or copper(I)oxide in the presence of a base, e. g., potassium phosphate, sodium tert-butylate or cesium carbonate, and optionally a diol ligand, e. g., 1,2-ethanediol, in a solvent such as 2-propanol or N-methylpyrrolidinone, at temperatures between 60°C and 150°C.
  • a copper(I) salt e. g., copper(I)iodide
  • copper(I)oxide in the presence of a base, e. g., potassium phosphate, sodium tert-butylate or cesium carbonate
  • a diol ligand e. g., 1,2-ethanediol
  • a solvent such as 2-propanol or N-methylpyrrolidin
  • the reaction may be performed with halide A-Hal in the presence of a palladium source, e. g., palladium(II)chloride or palladium(II)acetate, and a phosphine ligand, e. g., 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl or 2',4',6'-triisopropyl-1,1'-biphenyl-2-yldicyclohexylphosphine, a base, e. g., potassium phosphate, sodium methylate, or cesium carbonate, in a solvent such as toluene or 1,4-dioxane, at temperatures between 20°C and 110°C.
  • a palladium source e. g., palladium(II)chloride or palladium(II)acetate
  • a phosphine ligand e. g.,
  • reaction may be performed with boronic acid A-B(OH) 2 in the presence of anhydrous copper(II)acetate, in the presence of a base, e. g., triethylamine or pyridine, in a solvent such as dichloromethane, at temperatures between 0°C and 40°C, optionally in the presence of molecular sieves.
  • a base e. g., triethylamine or pyridine
  • a solvent such as dichloromethane
  • Amines of formula 1 can be synthesised from compounds of formula 2.
  • PG 1 is a suitable protective group, e. g., benzyl or benzyloxycarbonyl, E, F, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , V, W and n are as defined before.
  • the deprotection from 2 to 1 is performed, e. g., by hydrogenation at pressures between 1 bar and 10 bar, in solvents such as methanol, ethanol, tetrahydrofuran, ethyl acetate, or mixtures thereof, in the presence of a suitable catalyst, e. g., palladium on activated charcoal.
  • solvents such as methanol, ethanol, tetrahydrofuran, ethyl acetate, or mixtures thereof.
  • a suitable catalyst e. g., palladium on activated charcoal.
  • PG 1 is a suitable protective group, e. g., benzyl or benzyloxycarbonyl, E, F, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , V and n are as defined before.
  • PG 1 is a suitable protective group, e. g., benzyl or benzyloxycarbonyl, E, F, G, V, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and n are as defined before.
  • step a alkene 3 is converted to aldehyde 5 using methods and reagents known in the art.
  • the reaction is performed in with sodium periodate in the presence of catalytic amounts of a suitable osmium source such as osmium(VIII) oxide or potassium osmate(VI) dihydrate, in solvents such as acetone, tert-butylalcohol, water, or mixtures thereof, at temperatures between 0°C and 30°C.
  • a suitable osmium source such as osmium(VIII) oxide or potassium osmate(VI) dihydrate
  • solvents such as acetone, tert-butylalcohol, water, or mixtures thereof
  • aldehyde 5 is produced from alcohol 4 using methods and reagents known in the art.
  • the oxidation is carried out with sodium hypochlorite, in a two-phase mixture of water and dichloromethane, in the presence of sodium hydrogencarbonate and catalytic amounts of sodium bromide or potassium bromide and 2,2,6,6-tetramethylpiperidine-1-oxyl radical, at temperatures between 0°C and 25°C.
  • the oxidation can be performed with trichloroisocyanuric acid in the presence of catalytic amounts of 2,2,6,6-tetramethylpiperidine-1-oxyl radical, in a solvent such as dichloromethane, at temperatures between 0°C and 40°C.
  • dimethyl sulfoxide-based reagents can be employed, such as dimethyl sulfoxide-oxalyl chloride, or dimethyl sulfoxidetrifluoroacetic anhydride, in the presence of an organic base such as triethylamine in a solvent such as dichloromethane, at temperatures below 0°C, typically between -78°C and -60°C.
  • step b aldehyde 5 is converted to amine 2A by reductive amination reaction with amine HN(R 6 )(R 7 ).
  • the reaction is carried out using a suitable reducing agent, e. g., sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, or borane pyridine complex, in solvents such as methanol, ethanol, acetic acid, 1,2-dichloroethane, or mixtures thereof, optionally in the presence of a dehydrating agent such as magnesium sulfate, at temperatures between 0°C and 80°C.
  • a suitable reducing agent e. borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, or borane pyridine complex
  • solvents such as methanol, ethanol, acetic acid, 1,2-dichloroethane, or mixtures thereof, optionally in the presence of a dehydrating agent such as magnesium sulfate, at
  • PG 1 , E, F, G, V, R', R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and n are as defined before.
  • PG 1 is a suitable protective group, e. g., benzyl or benzyloxycarbonyl, E, F, G, V, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and n are as defined before.
  • PG 1 is a suitable protective group, e. g., benzyl or benzyloxycarbonyl, E, F, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , V and n are as defined before.
  • step a alkene 3 is oxidised to carboxylic acid 6 using reagents and methods known in the art.
  • the reaction is performed using sodium periodate in the presence of catalytic amounts of ruthenium(III) chloride, in a solvent mixture composed of carbon tetrachloride, acetonitrile, and water, at temperatures between 0°C and 40°C.
  • carboxylic acid 6 is produced from alcohol 4 using reagents and methods known in the art.
  • the reaction is performed using sodium chlorite in the presence of catalytic amounts of sodium hypochlorite and 2,2,6,6-tetramethylpiperidine-1-oxyl radical, in a buffered (preferably phosphate buffer at pH around 7) solvent mixture of water and acetonitrile, at temperatures between 30°C and 70°C.
  • a buffered preferably phosphate buffer at pH around 7
  • step b carboxylic acid 6 is converted to amide 2B by reaction with amine HN(R 6 )(R 7 ), using reagents and methods known in the art.
  • the reaction is carried out in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between 0°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, or 4-methylmorpholine, and in the presence of a coupling agent such as N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate, O-(
  • PG 1 , E, F, G, V, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and n are as defined before.
  • PG 1 is a suitable protective group, e. g., benzyl or benzyloxycarbonyl, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 V, W, and n are as defined before.
  • PG 1 is a suitable protective group, e. g., benzyl or benzyloxycarbonyl
  • R e is lower alkyl, e. g., methyl or ethyl
  • G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 V, W, and n are as defined before.
  • carbonyl compound 7 reacts in a condensation reaction with amino alcohol 8 , leading to amino ester 9 , which spontaneously cyclises to bicyclic lactam 2C .
  • the reaction is performed in a suitable solvent, e. g., toluene, at temperatures between 40°C and the boiling point of the solvent.
  • PG 1 , G, R e , R 1 , R 2 , R 1 , R 4 , R 5 , R 6 , R 7 V, W, and n are as defined before.
  • Amino alcohols 8 can be prepared as described in the experimental section.
  • Carbonyl compounds 7 can be synthesised as described in scheme 4.
  • PG 1 is a suitable protective group, e.g., benzyl or benzyloxycarbonyl
  • R e is methyl, ethyl, or tert-butyl
  • R f is lower alkyl, e. g., methyl or ethyl
  • Hal is chlorine, bromine or iodine
  • R 1 , R 2 , R 4 and R 5 are as defined before.
  • aldehyde or ketone 10 undergoes a reductive amination reaction with amine 11, leading to 12.
  • Suitable reagents for this conversion are borohydride reagents, e. g., sodium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride.
  • the reaction is performed solvents such as methanol, dichloromethane, 1,2-dichloroethane, acetic acid, water, or mixtures thereof, at temperatures between -20°C and 50°C, optionally in the presence of dehydrating agents such as magnesium sulfate or molecular sieves.
  • step b secondary amine 12 is converted to protected derivative 13 using methods and reagents known in the art.
  • PG 1 is benzyloxycarbonyl
  • the reaction is performed using benzyl chloroformate in the presence of a base, e. g., sodium hydrogencarbonate, in solvents such as acetone, tetrahydrofuran, water, or mixtures thereof, at temperatures between 0°C and 30°C.
  • a base e. g., sodium hydrogencarbonate
  • step c scheme 4, the acetal group of 13 is cleaved, leading to carbonyl compound 7.
  • the reaction is performed in the presence of an acidic catalyst, e. g., hydrochloric acid, formic acid, toluene 4-sulfonic acid, or pyridinium toluene 4-sulfonate, in a solvent such as water, methanol, acetone, 2-butanone or mixtures thereof, at temperatures between 0°C and 100°C.
  • an acidic catalyst e. g., hydrochloric acid, formic acid, toluene 4-sulfonic acid, or pyridinium toluene 4-sulfonate
  • step d scheme 4, aldehyde or ketone 14 undergoes a reductive amination reaction with amine 11, leading to 15. This reaction is performed in analogy with scheme 4, step a.
  • step e scheme 4, secondary amine 15 is converted to protected derivative 16. This reaction is performed in analogy with scheme 4, step b.
  • step f scheme 4, the alkene subunit of 16 is converted to a carbonyl group, leading to 7.
  • This reaction is performed using methods and reagents known in the art. For instance, the reaction is performed in with sodium periodate in the presence of catalytic amounts of a suitable osmium source such as osmium(VIII) oxide or potassium osmate(VI) dihydrate, in solvents such as acetone, tert-butylalcohol, water, or mixtures thereof, at temperatures between 0°C and 30°C.
  • a suitable osmium source such as osmium(VIII) oxide or potassium osmate(VI) dihydrate
  • solvents such as acetone, tert-butylalcohol, water, or mixtures thereof
  • compounds 7 can be synthesised as outlined in scheme 4, step g.
  • compound 17 is alkylated with halide 18.
  • This reaction is performed in the presence of a suitable base, e. g., sodium hydride, potassium tert-butylate, sodium carbonate, or sodium hydrogencarbonate, in a solvent such as tetrahydrofuran, 1,4-dioxane, water, N,N-dimethylformamide, or mixtures thereof, at temperatures between 0°C and 100°C.
  • a suitable base e. g., sodium hydride, potassium tert-butylate, sodium carbonate, or sodium hydrogencarbonate
  • solvent such as tetrahydrofuran, 1,4-dioxane, water, N,N-dimethylformamide, or mixtures thereof, at temperatures between 0°C and 100°C.
  • PG 1 is a suitable protective group, e. g., benzyl or benzyloxycarbonyl, G, R', R 2 , R 3 , R 4 , R 5 , V, and n are as defined before.
  • Compounds of formula 4A can be produced by thermal condensation of carbonyl compound 7 with amino alcohol 19, in analogy with scheme 3.
  • Amino alcohols 19 are commercially available or can be synthesised as outlined in the experimental section.
  • PG 1 , R e , G, R 1 , R 2 , R 3 , R 4 , R 5 , V, and n are as defined before.
  • PG 1 , PG 2 , and PG 3 are suitable protective groups - for instance, PG 1 is benzyloxycarbonyl, PG 2 is tert-butoxycarbonyl, and PG 3 is tetrahydropyran-2-yl.
  • R e is methyl, ethyl, or tert-butyl, m is an integer of 1 to 3, F, G, R 1 , R 2 , R 3 , R 4 and R 5 are as defined before.
  • step a scheme 6, aldehyde or ketone 20A, 20B, or 20C undergoes a reductive amination reaction with amino ester 11, leading to 21A, 21B, and 21C, respectively.
  • This reaction is performed in analogy with scheme 4, step a.
  • step b scheme 6, secondary amine 21A, 21B, or 21C is converted to protected derivative 22A, 22B, and 22C, respectively.
  • This reaction is performed in analogy with scheme 4, step b.
  • step c compound 22A is transformed into 3B.
  • This conversion is performed in two steps.
  • R e is methyl or ethyl
  • PG 2 is tert-butoxycarbonyl
  • PG 2 is cleaved under acidic conditions, e. g., using hydrogen chloride in 1,4-dioxane or trifluoroacetic acid in dichloromethane at temperatures between 0°C and 25°C.
  • the resultant amino ester is cyclised in the presence of a base, e. g., potassium carbonate, in a solvent such as methanol, at temperatures between 0°C and 60°C.
  • both R e and PG 2 are cleaved under acidic conditions as described above, i. e., using hydrogen chloride in 1,4-dioxane or trifluoroacetic acid in dichloromethane at temperatures between 0°C and 25°C.
  • the resultant amino acid is condensed to lactam 3B using methods and reagents known in the art, e.
  • a suitable coupling agent such as N,N'-dicyclohexylcarbodiimide or O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate, in the presence of a base, e. g., triethylamine or 4-methylmorpholine, in a solvent such as tetrahydrofuran or N,N-dimethylfomiamide, at temperatures between 0°C and 60°C.
  • a base e. g., triethylamine or 4-methylmorpholine
  • 22B is transformed into 4B in scheme 6, step c.
  • step c 22C is transformed into 4B in scheme 6, step c.
  • PG 3 is tetrahydropyran-2-yl
  • PG 3 is cleaved concomitantly with PG 1 and PG 2 , as described above.
  • Compound of formula 22B can be synthesised from 22A as outlined in scheme 7.
  • PG 1 and PG 2 are suitable protective groups - for instance, PG 1 is benzyloxycarbonyl and PG 2 is tert-butoxycarbonyl R e is methyl, ethyl, or tert-butyl.
  • m is an integer of 1 to 3
  • F, G, R 1 , R 2 , R 3 , R 4 and R 5 are as defined before.
  • alkene 22A is converted to alcohol 22B through a hydroboration reaction, using reagents and conditions described in the art.
  • the reaction is performed in the presence of9-borabicyclo[3.3.1]nonane in a solvent such as tetrahydrofuran, at temperatures between 0°C and 30°C, followed by oxidation of the 9-borabicyclo[3.3.1]non-9-yl adduct with hydrogen peroxide or sodium perborate, in solvents such as water, methanol, tetrahydrofuran, or mixtures thereof, at temperatures between 0°C and 30°C.
  • solvents such as water, methanol, tetrahydrofuran, or mixtures thereof
  • PG 2 and PG 3 are suitable protective groups; for instance PG 2 is tert-butoxycarbonyl and PG 3 is tetrahydropyran-2-yl, m is an integer of 1 to 3, R g is methyl, ethyl or benzyl, F, G, R 1 , R 2 and R 3 , are as defined before.
  • step a scheme 8, ester 21A, 21B, or 21C are reduced to alcohol 22A, 22B, and 22C, respectively.
  • This reaction is performed under suitable conditions, e. g., using lithium aluminum hydride in tetrahydrofuran or diethyl ether, or using sodium borohydride or lithium borohydride in methanol or tetrahydrofuran, at temperatures between -50°C and +50°C.
  • step b scheme 8
  • alcohol 22A, 22B, or 22C is oxdised to aldehyde 20A, 20B, and 22C, respectively, using methods and reagents known in the art.
  • the reaction is performed using dimethyl sulfoxide-based reagents such as dimethyl sulfoxide-oxalyl chloride or dimethyl sulfoxide-trifluoroacetic anhydride, in the presence of an organic base such as triethylamine in a solvent such as dichloromethane, at temperatures below 0°C, typically between -78°C and -60°C.
  • reaction is performed in the presence of 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane), in a suitable solvent such as dichloromethane or acetonitrile, at temperatures between 0°C and 50°C.
  • a suitable solvent such as dichloromethane or acetonitrile
  • compounds of formula 20A, 20B, and 20C in which R 1 is H can be synthesised directly from esters 21A, 21B and 21C, respectively using a suitable reducing agent, e. g., diisobutylaluminum hydride, in a solvent such as tetrahydrofuran or dichloromethane, at temperatures between -78°C and 0°C.
  • a suitable reducing agent e. g., diisobutylaluminum hydride
  • solvent such as tetrahydrofuran or dichloromethane
  • esters 21A, 21B, or 22C are converted into N-methoxy-N-methylamides 23A, 23B, and 23C, respectively, using methods and reagents known in the art. For instance, the reaction is performed using N,O-dimethylhydroxylamine in the presence of trimethylaluminum, in a solvent such as dichloromethane, at temperatures between -20°C and +30°C.
  • N-methoxy-N-methylamides 23A, 23B, or 23C are transformed into ketones of formula 20A, 20B, and 20C, respectvely, using methods and reagents known in the art.
  • the reaction is performed using organolithium (R 1 -Li) or organomagnesium (R 1 -Mg-Hal, Hal is Cl, Br, or I) reagents, in a solvent such as tetrahydrofuran, at temperatures between -78 °C and +70°C.
  • PG 2 , PG 3 , R g , F, G, R 1 , R 2 and R 3 are as defined before.
  • R g is methyl, ethyl, tert-butyl or benzyl
  • PG 2 is a suitable protective group, e.g ., tert-butoxycarbonyl
  • m is an integer of 1 to 3
  • F, G, R 2 and R 3 are as defined before.
  • step a scheme 9, alkene 21A is converted to alcohol 21B through a hydroboration reaction, in analogy with scheme 7.
  • step b scheme 9, alcohol 21B protected, leading to 21C.
  • PG 3 is tetrahydropyran-2-yl
  • the reaction is performed using 3,4-dihydro-2H-pyran in the presence of a suitable catalyst, e. g., toluene 4-sulfonic acid or pyridinium toluene-4-sulfonate, in a solvent such as dichloromethane, at about room temperature.
  • a suitable catalyst e. g., toluene 4-sulfonic acid or pyridinium toluene-4-sulfonate
  • PG 2 is a suitable protective group, e.g ., tert-butoxycarbonyl
  • R g is methyl, ethyl, tert-butyl or benzyl
  • m is an integer of 1 to 3
  • F, G, R 2 and R 3 are as defined before.
  • ester 24 is functionalised at the acidic ⁇ -position using methods known in the art. For instance, in the case where R 2 is alkyl or cycloalkyl, ester 24 is deprotonated using a suitable base, e.
  • PG 2 is a suitable protective group, e. g., tert-butoxycarbonyl, R g is methyl, ethyl, tert-butyl or benzyl, m is an integer of 1 to 3, F, G and R 3 are as defined before.
  • step a scheme 11, compound 25 is protected at the amide N-H, leading to 26.
  • PG 2 is tert-butoxycarbonyl
  • the reaction is performed using di-tert-butyl dicarbonate, in the presence of triethylamine, 4-(dimethylaminopyridine) or mixtures thereof, in solvents such as dichloromethane or acetonitrile, at temperatures between 0°C and 30°C.
  • step b scheme 11
  • This reaction is performed in a suitable solvent, e. g., tetrahydrofuran, at temperatures between -78°C and 0°C.
  • step c scheme 11, compound 27 is deprotected and cyclised to 28.
  • This reaction is performed in the presence of a suitable acid, e. g., trifluoroacetic acid, in a solvent such as dichloromethane, at temperatures between -20°C and +30°C.
  • a suitable acid e. g., trifluoroacetic acid
  • a solvent such as dichloromethane
  • step d imine 28 is reacted with a Grignard reagent of the general formula R 3 -Mg-Hal (Hal is Cl, Br or I), leading to 29.
  • a Grignard reagent of the general formula R 3 -Mg-Hal Hal is Cl, Br or I
  • This reaction is performed in a suitable solvent, e. g., tetrahydrofuran, at temperatures between -78°C and 0°C, optionally in the presence of a Lewis acid such as boron trifluoride etherate.
  • step e scheme 11
  • secondary amine 29 is protected, leading to 24.
  • PG 2 is tert-butoxycarbonyl
  • the reaction is performed using reagents and conditions described in the art, e. g., using di tert-butyl dicarbonate in a solvent such as dichloromethane.
  • PG 2 is a suitable protective group, e. g., tert-butoxycarbonyl, m is an integer of 1 to 3, R g is methyl, ethyl, tert-butyl or benzyl.
  • Compounds of formula 24A can be synthesised from compound 27 (scheme 11) by reaction with a silane reagent, e. g., triphenylsilane or triethylsilane, in the presence of a suitable Lewis acid, preferably tris(pentafluorophenyl)borane, in a solvent such as tetrahydrofuran, at temperatures between -78°C and +30°C.
  • a silane reagent e. g., triphenylsilane or triethylsilane
  • a suitable Lewis acid preferably tris(pentafluorophenyl)borane
  • solvent such as tetrahydrofuran
  • Compound of formula 24A can also be synthesised as outlined in scheme 12.
  • PG 2 is a suitable protective group, e. g., tert-butoxycarbonyl, R g is methyl, ethyl, tert-butyl or benzyl, F and G are as defined before.
  • step a scheme 12
  • compound lactone 25 is reduced to lactol 30, using reagents and conditions known in the art.
  • the reaction is performed in the presence of a suitable reducing agent, e. g., lithium triethylborohydride, in a solvent such as tetrahydrofuran, at temperatures between -78°C and 0°C.
  • a suitable reducing agent e. g., lithium triethylborohydride
  • step b scheme 12
  • lactol 30 is converted to compound 31, using reagents and methods known in the art.
  • the reaction is performed in the presence of a suitable acid, e. g., toluene 4-sulfonic acid, in methanol, at temperatures between 0°C and the boiling point of the solvent.
  • a suitable acid e. g., toluene 4-sulfonic acid
  • step c compound 31 is transformed into 24A, using reagents and methods known in the art.
  • This reaction is performed in a suitable solvent, e. g., tetrahydrofuran or diethyl ether, at temperatures between -78°C and 0°C, in the presence of copper(I) bromide dimethylsulfide complex and boron trifluoride etherate.
  • the reaction is preferably performed with allyltrimethylsilane, in the presence of a Lewis acid such as boron trifluoride etherate, at temperatures between -78°C and 0°C.
  • a Lewis acid such as boron trifluoride etherate
  • PG 2 is a suitable protective group, e. g., tert-butoxycarbonyl, R g is methyl, ethyl, tert-butyl or benzyl.
  • R g is methyl, ethyl, tert-butyl or benzyl.
  • the reaction is performed in analogy with scheme 4, step f.
  • this conversion is accomplished through ozonolysis, in solvents such as dichloromethane, methanol or mixtures thereof, at temperatures between -78°C and 0°C, followed by work-up with dimethylsulfide.
  • Compounds of formula I can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • the optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbent or eluent). The invention embraces all of these forms.
  • the compounds of formula (I) are CCR2 receptor antagonists, with some antagonist activity also at CCR3 and CCR5. These compounds consequently prevent migration of various leukocyte populations through the blockade of CCR2 stimulation. They therefore can be used for the treatment and/or prevention of inflammatory and/or allergic diseases, such as peripheral arterial occlusive disease, critical limb ischemia (CLI), vulnerable atherosclerotic plaque patients, unstable angina, congestive heart failure, left ventricular hypertrophy, ischemia reperfusion injury, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetes and diabetic complications, diabetic nephropathy, irritable bowel syndrome, Crohn's disease, multiple sclerosis, neuropathic pain, atherothrombosis and/or burns/ulcers in diabetes/CLI, and asthma.
  • inflammatory and/or allergic diseases such as peripheral arterial occlusive disease, critical limb ischemia (CLI), vulnerable atherosclerotic plaque patients, unstable angina, con
  • the invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable excipient.
  • the invention likewise embraces compounds as described above for use as therapeutically active substances, especially as therapeutically active substances for the treatment and/or prophylaxis of inflammatory and/or allergic diseases, particularly as therapeutically active substances for the treatment and/or prophylaxis of peripheral arterial occlusive disease, critical limb ischemia, vulnerable atherosclerotic plaque patients, unstable angina, congestive heart failure, left ventricular hypertrophy, ischemia reperfusion injury, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable bowel syndrome, Crohn's disease, multiple sclerosis, neuropathic pain, atherothrombosis, burns/ulcers in diabetes/CLI, and allergy, asthma.
  • the invention also relates to the use of compounds as described above for the preparation of medicaments for the therapeutic and/or prophylactic treatment of inflammatory and/or allergic diseases, particularly for the therapeutic and/or prophylactic treatment of peripheral arterial occlusive disease, critical limb ischemia, vulnerable atherosclerotic plaque patients, unstable angina, congestive heart failure, left ventricular hypertrophy, ischemia reperfusion injury, stroke, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable bowel syndrome, Crohn's disease, multiple sclerosis, neuropathic pain, atherothrombosis, burns/ulcers in diabetes/CLI, and asthma.
  • Such medicaments comprise a compound as described above.
  • the invention also relates to the process and the intermediates for manufacturing the compounds of formula (I) as well as the process for manufacturing the intermediates.
  • CCR2 receptor antagonistic activity by the compounds of the present invention can be demonstrated by the following assays.
  • Binding assays were done with membranes from CHOK1-CCR2B-A5 cells (Euroscreen) stably overexpressing the human CCR2B.
  • Membranes were prepared by homogenizing the cells in 10 mM Tris pH 7.4, 1 mM EDTA, 0.05 mM benzamidine, leupeptin 6mg/L and separating the debris at 1000g. The membranes were then isolated at 100000g in 50 mM Tris pH 7.4, MgCl 2 10 mM, EGTA 1 mM, glycerol 10%, benzamidine 0.05 mM, leupeptine 6mg/l.
  • CCR2 antagonist compounds were added in various concentrations in 50 mM HEPES pH 7.2, 1 mM CaCl 2 , 5mM MgCl 2 , 0.5% BSA, 0.01% NaN 3 , together with 100pM 125 I-MCP-1 (PerkinElmer, 2200Ci/mmol) to about 5 fMol CCR2 membranes and incubated for 1 hour at room temperature.
  • 100pM 125 I-MCP-1 PerkinElmer, 2200Ci/mmol
  • Membranes were harvested through GF/B (glass fiber filter; PerkinElmer) plates, equilibrated with 0.3% polyethylenimine, 0.2% BSA, air dried and binding was determined by counting in a topcounter (NXT Packard). Specific binding was defined as total binding minus nonspecific binding and typically represents about 90-95% of the total binding. Antagonist activity is indicated as inhibitor concentration required for 50% inhibition (IC 50 ) of specific binding.
  • CHOK1-CCR2B-A5 cells (from Euroscreen) stably overexpressing the human chemokine receptor 2 isoform B were cultured in Nutrient Hams F12 medium supplemented with 5% FBS, 100U/ml penicillin, 100 ⁇ g/ml streptomycin, 400 ⁇ g/ml G418 and 5 ⁇ g/ml puromycin.
  • Test compounds were added to the assay plate and agonist activity was monitored as fluorescence for 80 seconds with a FLIPR (488 nm excitation; 510-570 nm emission; Molecular Devices). After 20-30 min. of incubation at 30 °C, 20 nM MCP-1 (R&D; Roche) was added and fluorescence was monitored again for 80 seconds. Increases in intracellular calcium are reported as maximum fluorescence after agonist exposure minus basal fluorescence before exposure. Antagonist activity is indicated as inhibitor concentration required for 50% inhibition of specific calcium increases.
  • the compounds I of the present invention exhibit IC 50 values in the Ca mobilisation assay of 1 nM to 10 ⁇ M, preferably 1 nM to 1.5 ⁇ M for CCR2.
  • the following table shows measured values for some selected compounds of the present invention.
  • Example IC50 ( ⁇ M) 1 0.0058 2 0.0022 3 0.0604 4 0.0160 5 0.0679 6 0.0720 7 0.0250 8 0.1463 9 0.0689 12 0.0120 13 0.0127 14 0.0111 15 0.0328 16 0.0074 17 0.0029 18 0.0102 19 0.0334 20 0.1766 21 0.0038 22 0.0274 23 0.0144 24 0.0055 25 0.0200 26 0.0618 27 0.0494 28 0.0037 29 0.7743 30 0.0015 31 0.0019 32 0.0021 33 0.0027 35 0.0057 36 0.0093 37 0.3604 38 0.0088 39 0.1354 40 0.3404 41 0.0033 42 0.0404 43 0.0205 44 0.4732 45 0.1996 46 0.0264 47 0.0674 49 0.1443 51 0.
  • the compounds of formula (I) and/or their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the forum of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or suspensions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils. Oral administration is preferred.
  • the production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials.
  • lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragées and hard gelatine capsules.
  • Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers might, however, be required in the case of soft gelatine capsules).
  • Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar.
  • Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils.
  • Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
  • Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
  • Usual stabilizers preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
  • the dosage of the compounds of formula (I) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 to 1000 mg, especially about 1 to 300 mg, comes into consideration. Depending on severity of the disease and the precise pharmacokinetic profile the compound could be administered with one or several daily dosage units, e.g. in 1 to 3 dosage units.
  • the pharmaceutical preparations conveniently contain about 1-500 mg, preferably 1-100 mg, of a compound of formula (I).
  • aq. aqueous
  • Boc tert-butoxycarbonyl
  • DCM dichloromethane
  • DMF N,N- dimethylformamide
  • Et 3 N Triethylamine
  • EtOAc ethyl acetate
  • EtOH Ethanol
  • HOAc acetic acid
  • HPLC high-pressure liquid chromatography
  • ISP ion spray
  • MeOH methanol
  • MS mass spectrometry
  • sat. saturated
  • THF tetrahydrofuran.
  • 2,2,6,6,-Tetramethylpiperidine-1-oxyl radical (0.05 mg, 0.3 ⁇ mol) was added at room temperature to a suspension of (3S,5S)-5-hydroxymethyl-3-methyl-4-oxo-octahydro-9-oxa-2,4a-diaza-benzocycloheptene-2-carboxylic acid benzyl ester (example 23B, 102 mg, 0.29 mmol) and trichloroisocyanuric acid (72 mg, 0.29 mmol) in DCM (1 mL), then after 5 min the mixture was washed with 1 M aq. sodium sulfite solution and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated.
  • the title compound was produced in analogy with example 28A from (4S,7S)-4-hydroxymethyl-7-methyl-6-oxo-hexahydro-pyrazino[2,1-b][1,3]oxazine-8-carboxylic acid benzyl ester by oxidation to (4S,7S)-4-oxomethyl-7-methyl-6-oxo-hexahydro-pyrazino[2,1-b][1,3]oxazine-8-carboxylic acid benzyl ester, which was subjected to a reductive amination reaction with (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride. Light yellow gum, MS: 444.3 (M+H) + .
  • Lithium triethylborohydride solution (1 M in THF, 11.2 mL, 11.2 mmol) was added dropwise at-78°C to a solution of 1-(tert-butoxycarbonyl)-R-6-oxopipecolic acid methyl ester ( J. Org. Chem. 1996, 61, 8496 ; 2.40 g, 9.33 mmol) in THF (30 mL), then after 90 min the reaction mixture was poured upoin half-saturated aq. sodium hydrogencarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated.
  • reaction mixture was stirred for another 45 min at 0°C, then methanol (80 mL), water (115 mL) and sodium perborate tetrahydrate (37.3 g, 242 mmol) were added. After 90 min the ice bath was removed, then after stirring for 16 h the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO 2 ; heptane - ethyl acetate gradient) afforded the title compound (3.76 g, 81%). Colourless gum, MS: 537.5 (M+H) + .
  • Film coated tablets containing the following ingredients can be manufactured in a conventional manner: Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0 mg Polyvinylpyrrolidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titanium dioxide 0.8 mg 1.6 mg
  • the active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water.
  • the granulate is mixed with sodium starch glycolate and magesiumstearate and compressed to yield kernels of 120 or 350 mg respectively.
  • the kernels are lacquered with an aqueous solution / suspension of the above mentioned film coat.
  • Capsules containing the following ingredients can be manufactured in a conventional manner: Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg
  • the components are sieved and mixed and filled into capsules of size 2.
  • Injection solutions can have the following composition: Compound of formula (I) 3.0 mg Polyethylene glycol 400 150.0 mg Acetic acid q.s. ad pH 5.0 Water for injection solutions Ad 1.0 ml
  • the active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (part).
  • the pH is adjusted to 5.0 by acetic acid.
  • the volume is adjusted to 1.0 ml by addition of the residual amount of water.
  • the solution is filtered, filled into vials using an appropriate overage and sterilized.
  • Soft gelatin capsules containing the following ingredients can be manufactured in a conventional manner: Capsule contents Compound of formula (I) 5.0 mg Yellow wax 8.0 mg Hydrogenated soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0 mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg Gelatin capsule Gelatin 75.0 mg Glycerol 85 % 32.0 mg Karion 83 8.0 mg (dry matter) Titanium dioxide 0.4 mg Iron oxide yellow 1.1 mg
  • the active ingredient is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size.
  • the filled soft gelatin capsules are treated according to the usual procedures.
  • Sachets containing the following ingredients can be manufactured in a conventional manner: Compound of formula (I) 50.0 mg Lactose, fine powder 1015.0 mg Microcrystalline cellulose (AVICEL PH 102) 1400.0 mg Sodium carboxymethyl cellulose 14.0 mg Polyvinylpyrrolidone K 30 10.0 mg Magnesiumstearate 10.0 mg Flavoring additives 1.0 mg
  • the active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water.
  • the granulate is mixed with magnesiumstearate and the flavouring additives and filled into sachets.

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